Lipoxygenases are non-heme, non-sulfur iron dioxygenases that act on lipid substrates containing one or more 1,4-pentadiene moieties to form hydroperoxides. 5-Lipoxygenase is a key enzyme that catalyses the first two steps in the oxygenation of arachidonic acid, which is converted to biologically active leukotrienes, namely leukotriene B4 (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 196-201(6)) and cysteinyl leukotrienes. Leukotrienes play important role in the pathophysiology of inflammatory/allergic diseases including bronchial asthma (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 264-273(10)), allergic rhinitis (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 235-243(9)), urticaria, atopic dermatitis (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 305-308(4)), chronic obstructive pulmonary disease (Eur. Respir. J., 2003, 22: 926-930). Incidence of allergic/inflammatory diseases are on the rise world over (Expert Opinion on Therapeutic Targets, Volume 3, Number 2, June 1999, pp. 229-240(12); Expert Opinion on Investigational Drugs, Volume 10, Number 7, 1 July 2001, pp. 1361-1379(19)).
A variety of stimuli, namely antigen-antibody reaction, cold or hypeosmotic shock etc, that elevates intracellular calcium level, can cause arachidonic acid release from cell membranes under the influence of cytosolic phospholipase A2. Arachidonic acid is transferred to nuclear membrane by 5-lipoxygenase binding protein (FLAP) and acted upon by 5-lipoxygenase enzyme to generate 5-hydroperoxyeicosatetraenoic acid (HPETE). HPETE is converted to LTA4 by 5-lipoxygenase. Depending upon cell type, LTA4 is converted to either cysteinyl leukotrienes and/or leukotriene B4 (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 196-201(6); Current Drug Targets—Inflammation & Allergy, Volume 1, Number 1, March 2002, pp. 23-44(22); Drug Safety, Volume 26, Number 7, 2003, pp. 483-518(36)).
Leukotrienes are generated by a variety of inflammatory cell types. Neutrophils and monocytes generate LTB4 whereas mast cells, basophils, eosinophils and bronchial epithelial cells produce cysteinyl leukotrienes. LTB4 acts as a chemo attractant for neutrophils through specific cell surface receptors. Cysteinyl leukotrienes, which include LTC4, LTD4 and LTE4, act on CysLT1 and CysLT2 receptors and increase bronchial smooth muscle contractility, promote mucosal secretion, increase vascular permeability and encourage eosinophils recruitment. (Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S210-S213; Thorax 2000, 55S32-S37; Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 196-201(6); Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 220-228(9); Drug Safety, Volume 26, Number 7, 2003, pp. 483-518(36)).
There is evidence suggesting that cysteinyl leukotrienes can increase airway smooth muscle contractility in preclinical studies (Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S214-S219) and clinical studies (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 220-228(9)). Inhalation of leukotrienes also increases influx of inflammatory cells in the airway of animals (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 220-228(9)) and humans (Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S210-S213). In patients with asthma, urinary excretion of LTE4 correlates with exercise or cold air induced bronchoconstriction (Lancet, 1, 584, 1989) allergen induced early and late phase response (Clinical & Experimental Allergy, Volume 28, Number 11, 1 Nov. 1998, pp. 1332-1339(8); Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S210-S213), as well as with reduction of FEV1 in patients with nocturnal asthma (Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S233-S237). Efficacy of leukotriene biosynthesis inhibitors and leukotriene receptor antagonists have been tested in numerous trails involving asthma patients (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 254-260(7); Drug Safety, Volume 26, Number 7, 2003, pp. 483-518(36); The New England Journal of Medicine, Volume 340:197-206, 1999; Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S233-S237).
Emerging evidence shows that leukotrienes also contribute towards pathophysiology of COPD. Two major cell types, neutrophils and macrophages, generate LTB4 and are modulated by the same; these cell types are believed to participate in the pathogenesis of COPD (Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, S210-S213). Patients with COPD exhibit elevated sputum neutrophilia and LTB4 levels (Chest. 2002; 121:197S-200S0. Elevated levels of LTB4 were shown to be present in the exhaled breath condensate of COPD patients (Thorax 2003; 58: 585-588) as well as in patients experiencing exacerbation of COPD (Thorax 2003; 58: 294-298). Inhibitors of leukotriene biosynthesis as well as LTB4 receptor antagonists have shown to reduce airway reactivity, airway inflammation and airway neutrophilia in animals (J. Clin. Exp. Aller. 91, 917, 1992; J. Pharmacol. Exp. Ther., 2001, 297: 458-466) as well as in human subjects (Thorax, 1996, 51: 1178-1184; Chest. 2002; 122: 289S-293S). Cysteinyl leukotriene antagonists, such as Montelukast, has shown protective effect in hypertonic saline induced bronchoconstriction in COPD patients (Eur. Respir. J., 2003, 22: 926-930).
Similarly, evidence is emerging based on animal and human data that leukotriene pathway modulators can play role in arthritis (J. Pharmacol. Exp. Ther., 1998, 285: 946-954), allergic rhinitis and urticaria (Clinical & Experimental Allergy Reviews, Volume 1, Number 3, November 2001, pp. 235-243(9)), cancer (Current Drug Targets—Inflammation & Allergy, Volume 3, Number 1, March 2004, pp. 19-33(15)), inflammatory bowel disease (Laboratory Investigation, 2005, 85, 808-822; Indian Journal of Experimental Biology Vol. 42, July 2004, pp. 667-673), acne (Dermatology 210(1), 36-38, 2005; Arch. Dermatol. 2003;139: 668-670), pruritis (J. Invest. Dermatol. 117, 1621, 2001), as well as atherosclerosis (N. Engl. J. Med. 2004, 350, 29-37; N. Engl. J. Med. 2004, 350, 4-7, Med. Res. Rev. 24, 399, 2004).
WO 96/14307, WO 96/40660, WO 98/03492 and WO 98/03494 disclose substituted benzylamine derivatives, which have been said to be useful in the diagnosis and treatment of feeding disorders such as obesity, bulimia and cardiovascular diseases such as essential hypertension and congestive heart failure due to the binding of these compounds to human Neuropeptide Y1 receptors.
WO 96/31485 discloses 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives, which have been said to have PDE IV and cytokine activity.
U.S. Pat. No. 5,883,106 discloses compounds, which have been described to have the ability to inhibit 5-lipoxygenase enzyme.
Several leukotriene receptor antagonists, Montelukast, Zafirlukast, and Pranlukast, and a 5-lipoxygenase inhibitor, Zileuton, has been launched in the market. Both categories of molecules have shown efficacy in clinical trials of bronchial asthma. Inhibitors of 5-lipoxygenase exhibit greater potential to exhibit efficacy in COPD as well because of their inhibitory effect on LTB4 mediated processes. However, commercially available 5-lipoxygenase inhibitor is associated with poor pharmacokinetic property and adverse events, such as elevation of hepatic transaminases. Thus, there remains a need for novel inhibitors of 5-lipoxygenase having improved pharmacokinetic profiles and reduced adverse effects.